The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy

Pain and Therapy, Nov 2015

Introduction We recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated that common OPRM1 polymorphisms may be responsible. This study investigated the association between 118A>G (dbSNP rs1799971) and IVS2+691G>C (dbSNP rs2075572) variants on cold pain responses among opioid-dependent Malay males on methadone maintenance therapy. Methods Cold pain responses including pain threshold, pain tolerance, and pain intensity were measured using the cold pressor test. DNA was extracted from the venous blood before polymerase chain reaction genotyping. Repeated measures analysis of variance was used to compare the cold pain responses and OPRM1 polymorphisms (118A>G and IVS2+691G>C) using models including genotype dominant and recessive models, allelic additive models, and analysis of haplotypes and diplotypes. Results A total of 148 participants were recruited. With the recessive model, those with IVS2+691 homozygous CC genotype had a shorter cold pain tolerance time than those without CC genotype (i.e., GG/GC genotype; 29.81 vs. 43.08 s, respectively, P = 0.048). On the other hand, with diplotype analysis, participants with combined homozygous 118 AA genotype and heterozygous IVS2+691 GC genotype (i.e., AC/AG diplotype) had a longer cold pain tolerance time than those without this diplotype (49.34 vs. 31.48 s, respectively, P = 0.043). Cold pain threshold was not associated with any of the 118A>G and IVS2+691G>C variations despite being analyzed using various models (all P > 0.05). Conclusion The IVS2+691 CC genotype and AC/AG diplotype of 118A>G and IVS2+691G>C seem to have opposing roles in pain tolerance among opioid-dependent Malay males on methadone therapy. Haplotypes of OPRM1 may be associated with altered binding affinity.

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The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy

Pain Ther The Opposing Roles of IVS2+691 CC Genotype and AC/ AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid- Dependent Malay Males on Methadone Therapy Nasir Mohamad . Rusli Ismail 0 1 2 3 4 5 6 7 Malay 0 1 2 3 4 5 6 7 0 C. S. Lee Department of Emergency Medicine, School of Medical Sciences , USM, Kota Bharu, Kelantan , Malaysia 1 Z. Zahari C. S. Lee M. A. Ibrahim N. Musa M. A. M. Yasin S. C. Tan N. Mohamad R. Ismail Pharmacogenetics and Novel Therapeutics Cluster, Institute for Research in Molecular Medicine (INFORMM) , Universiti Sains Malaysia (USM), Kota Bharu, Kelantan , Malaysia 2 Z. Zahari (&) Department of Pharmacy, Hospital Universiti Sains Malaysia , Kota Bharu, Kelantan , Malaysia 3 R. Ismail Centre of Excellence for Research in AIDS (CERiA), University of Malaya , Kuala Lumpur , Malaysia 4 N. Mohamad Faculty of Medicine and Health Sciences, Universiti Sultan Zainal Abidin , Kuala Terengganu, Terengganu , Malaysia 5 Y. Y. Lee School of Medical Sciences, Universiti Sains Malaysia , Kota Bharu, Kelantan , Malaysia 6 M. A. M. Yasin Department of Psychiatry, School of Medical Sciences , USM, Kota Bharu, Kelantan , Malaysia 7 M. A. Ibrahim Department of Pharmacology and Toxicology, College of Pharmacy, Hawler Medical University , Erbil , Iraq Introduction: We recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated investigated the association between 118A[G rs2075572) variants on cold pain responses among were measured using the cold pressor test. DNA was extracted from the venous blood before - that common OPRM1 polymorphisms may be responsible. This study Electronic supplementary material The online version of this article (doi:10.1007/s40122-015-0041-y) contains supplementary material, which is available to authorized users. chain reaction genotyping. Repeated measures analysis of variance was used to compare the cold pain responses and OPRM1 polymorphisms (118A[G and IVS2?691G[C) using models including genotype dominant and recessive models, allelic additive models, and analysis of haplotypes and diplotypes. Results: A total of 148 participants were recruited. With the recessive model, those with IVS2?691 homozygous CC genotype had a shorter cold pain tolerance time than those without CC genotype (i.e., GG/GC genotype; 29.81 vs. 43.08 s, respectively, P = 0.048). On the other hand, with diplotype analysis, participants with combined homozygous 118 AA genotype and heterozygous IVS2?691 GC genotype (i.e., AC/AG diplotype) had a longer cold pain tolerance time than those without this diplotype (49.34 vs. 31.48 s, respectively, P = 0.043). Cold pain threshold was not associated with any of the 118A[G and IVS2?691G[C variations despite being analyzed using various models (all P[0.05). Conclusion: The IVS2?691 CC genotype and AC/AG diplotype of 118A[G and IVS2?691G[C seem to have opposing roles in pain tolerance among opioid-dependent Malay males on methadone therapy. Haplotypes of OPRM1 may be associated with altered binding affinity. INTRODUCTION Malays; Methadone dependence; Pain The opioidergic neurotransmission system is an important processor of painful stimuli [1–4]. The l-opioid receptor (OPRM1) is a primary target for clinically important opioid analgesics, including methadone. Studies among healthy subjects showed a possible role of the opioid receptor mu 1 gene (OPRM1) in altered pain sensitivity [5, 6]. Genetic factors that affect the density, function, and, consequently, the signaling efficacy of l-opioid receptors may contribute to inter-individual variations in the pain response to opioids [7–9]. Southeast Asia is a highly populated and cultural-diverse region with ethnic Malays constituting the largest population group, mainly populating countries including Malaysia, Indonesia, and the southern part of the Philippines. Males who are ethnic Malays make up the majority of opioid-dependent patients on methadone treatment in Malaysia [ 10 ]. We have previously reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive and that the pain is frequently associated with poor sleep quality [ 11 ]. One postulated mechanism for altered pain sensitivity in this susceptible population is polymorphisms in the OPRM1 gene. Some of the most frequently studied polymorphisms of OPRM1 include 118A[G (dbSNP rs1799971), IVS2?691G[C (dbSNP rs2075572), and IVS2?31G[A (dbSNP rs9479757). The association between 118A[G polymorphism and pressure pain was first reported by Fillingim et al. [6] and Lotsch et al. [5], but subsequent studies failed to replicate these preliminary reports in different experimental pain models and in different populations [ 12–14 ]. Similarly, the roles of other polymorphisms on pain sensitivity, including IVS2?691G[C and IVS2?31G[A, have been mixed. For example, the IVS2?691G[C polymorphism did not increase mo (...truncated)


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Zalina Zahari, Chee Siong Lee, Muslih Abdulkarim Ibrahim, Nurfadhlina Musa, Mohd Azhar Mohd Yasin, Yeong Yeh Lee, Soo Choon Tan, Nasir Mohamad, Rusli Ismail. The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy, Pain and Therapy, 2015, pp. 179-196, Volume 4, Issue 2, DOI: 10.1007/s40122-015-0041-y